The kidneys may be affected in a variety of ways in the plasma cell dyscrasias; all of the important lesions result from the accumulation/deposition of the paraprotein in some or all of the renal components (Table 33–1). The different abnormalities are determined by properties of the paraprotein rather than the patient response. The kidneys may be the only organ affected [the lesion known as Bence Jones (myeloma) cast nephropathy] or may be part of systemic processes (amyloidosis, monoclonal immunoglobulin deposition disease). A diagnosis of a plasma cell dyscrasia is not always known prior to the discovery of abnormal kidney function. The renal biopsy, performed to identify the responsible lesion, is not infrequently the initial indication of a plasma cell dyscrasia. Although multiple myeloma (MM) may be diagnosed, it is important to appreciate that some of the disorders discussed here may be associated with either a monoclonal gammopathy of uncertain significance (MGUS) or only a minor increase in bone marrow plasma cells. The clinical manifestations depend on the type of renal involvement, the renal tissue component affected, and whether only one or more of the lesions are present. The definition of the specific lesion is dependent on the tissue pathologic features, for the clinical and laboratory findings often do not readily allow for a specific diagnosis.

Essentials of Diagnosis

• Heavy proteinuria.
  
• Renal insufficiency.
  
• Monoclonal free light chains (LCs) in serum or urine.
  
• Renal biopsy disclosing characteristic extracellular deposits.

General Considerations

A contemporary classification of systemic amyloidosis (AL), based on the nature of the amyloid protein that is deposited in tissue, is given in Table 33–2. Amyloidosis is a disorder of abnormal protein folding in which normally soluble proteins are deposited in tissues as fibrillar structures that disrupt organ function and produce disease. The proteins are folded into a β-pleated sheet form that results in a high affinity for Congo red and several other metachromatic dyes. Only one variety of amyloidosis is also a paraprotein, namely AL amyloidosis, in which the fibrils are composed of one or the other of the immunoglobulin LCs. Although this discussion will focus on only this form of systemic amyloidosis, it should be recalled that amyloid may also occur in a localized form. Identification of the precise biochemical nature of the amyloid fibril requires the examination of a tissue specimen with a combination of immunofluorescence or immunoperoxidase and often biochemical tests. Genetic testing may also be needed in the case of the hereditary amyloidoses.

Amyloidosis is an uncommon disease affecting about 12 patients per million population per year, with about 15% representing hereditary forms and the remaining consisting of acquired, nongenetic forms. Any race, sex, or ethnicity can be affected.

Pathogenesis

AL amyloid fibrils are derived from the N-terminal region (variable domain) of monoclonal immunoglobulin LCs, more commonly λ than κ. The AL amyloid fibrils can deposit in almost any tissue except the brain. Certain LCs are more “amyloidogenic” than others. Furthermore, differences in the variable region of the LC (λ) may determine the sites of amyloid deposition. VλVI results in dominant renal involvement while others (VλII or III) are more likely to have dominant cardiac or other organ involvement. AL amyloidosis is also known as primary amyloidosis, largely a holdover from the older literature. A truncated monoclonal heavy chain may rarely cause amyloid (known as AH amyloid).

The fibrils in AL amyloidosis are composed of fragments of the variable portion of monoclonal LCs (λ more frequently than κ). In AA amyloidosis the fibrils are composed of the serum Amyloid A protein. In hereditary Amyloidosis the fibrils are composed of the mutant protein (e.g., Fibrinogen alpha chain). These can be differentiated by appropriate immunohistological studies of biopsy tissue (see below). As monoclonal LCs may deposit in tissue and result in another disease (see monoclonal immunoglobulin deposition disease), it is clear that an additional factor is necessary to form the characteristic morphologic features of amyloid. It is likely that the LCs need to be phagocytized by macrophages where the LCs are metabolized to preamyloid fragments that are secreted and precipitate in the tissues. In the kidneys, the major site of accumulation is the glomeruli, with arterioles, arteries, interstitium, and tubular basement membranes involved to somewhat lesser degrees.

Clinical Findings

Symptoms and Signs

Almost any B cell dyscrasia can be associated with AL amyloidosis, which develops in about 10–15% of cases of MM. Most cases of AL amyloidosis are not associated with MM, but rather develop in association with MGUS or as a “primary” disorder. A monoclonal paraprotein of free LCs can be detected in the serum or urine of the majority of patients. Because older patients may not infrequently (5–10%) have an MGUS, it is necessary to be cautious not to overinterpret the significance of a small paraprotein “spike” in a serum protein electrophoresis.

Bone marrow aspirates or biopsies may reveal frank MM, but frequently do not. The disorder develops equally in men and women, but is quite uncommon in individuals <40 years of age. The clinical manifestations, which depend on the site or sites of amyloid deposition, can be quite varied. Cardiac [heart failure due to restrictive cardiomyopathy, atrioventricular (AV) nodal disease, or “pseudoinfarct” or low-voltage patterns on EKG], renal (nephrotic syndrome, symptomatic proteinuria, renal failure), tongue (macroglossia), gastrointestinal (malabsorption, motility disorders), peripheral nerve [sensory (“stocking and glove”) and motor neuropathies, carpal tunnel syndrome], autonomic nerves (orthostatic hypotension, impotence, gastroparesis), skin (papules, nodules, purpura, ecchymoses with minimal trauma), joints (polyarthritis of the shoulder girdle), and coagulation (Factor IX and X deficiency with bleeding) are among the most common. Macroglossia is almost pathognomonic of AL amyloidosis. Patients presenting with unexplained proteinuria (including nephrotic syndrome), nonischemic cardiac failure, peripheral neuropathy, or hepatomegaly after age 40 years should always be suspected of having AL amyloidosis. Hypertension and hematuria are said to be uncommon in renal amyloidosis, but severe hypertension may be present when renal failure ensues, and normomorphic hematuria due to bladder involvement with amyloid may occur. Renal involvement is principally heralded by proteinuria, which sometimes can be massive (>20 g/day) and lead to problems of protein malnutrition, severe edema, and volume depletion.